Process for oxidizing unsaturated polycyclic alcohols



Patented Sept. 4, 1945 TATES PATENT OFFICE PROCESS FOR OmIZING UNSATUBATED ?LYCYCLIC ALCOHOLS Rupert Oppenauer, Amsterdam, Netherlands; vested in the Alien Property Custodian No Drawing. Application May 21, 1937, Serial No. ididlili. In the Netherlands May 26, 1936 oxidized the dibromide to the dibromoketone by phenanthrene nucleus, are reacted with an excess of an aldehyde or ketone in the presence of an alcoholate selected from a class consisting of aluminum alcoholate and chloro-magnesium alcoholate, the process being usually conducted at temperatures ranging from about 50 to 140 C. and in the presence of an inert solvent; all as more iully hereinafter set forth and as claimed.

The chemical investigation of hormones dur-- ing recent years has shown that a great number of these physiologically and pharmacologically important substances and particularly the sexhormones are polycyclic ketones. It has been found e. g. that progesteron which is the active substance of the corpus luteum extract is A-4,5 pregnendion (3,20) and that testosteron is A-4,5- androstenol-(l?) -on- (3) These and many other hormones which are polycyclic ketones have been also prepared synthetically from cholesterol, stigmasterol etc. such as, e. g. the progesteron means of 'KMnOr or Cr% and then eliminated the bromine from this dibromoketone. They also obtained in this way ayield. of cholestenon of 60 .to 65%. Both processes have already been applied to the preparation of polycyclic ketones from alcohols such as e. g. the oxidation by means of 0110 according to Diels in connection with the progesteron (Fernholz B. 67, 2030, 1934). In this way, however, a yield of only 4% was obtained which can be readily understood, bearing in mind the drastic treatment.

The second process (via the bromine de'rlvatives) is the method generally in use up till now for the synthesis of polycyclic unsaturated ketones. In this way crystallized progesteron e. g. was obtained from A-5, 6-pregnenol-(3)-onin a yield of 35-40% (Butenandt B. 69, 443, 1936).

v This method was also applied to the preparation of testosteron and methyl testosteron, however these reactions, which conditions are, however,

(Butenandt and cooperators Z. Physiol. Chem.

227, 84,1934, Ber. 67B, 1611, 2085, 1934, and Fernholz Ber. 67, 1855, 2027, 1934), the testosteron (Ruzicka and cooperators Helv. Chim. Acta 18, 1264, 1478, 1935), the methyltestosteron (Ruzicka,

Goldberg, Rosenberg Helv. Chim. Acta 18, 148.7,

1945), the androstendion (Ruzicka, Wettstein, Helv. Chim. Acta 18, 986, 1935) etc.

As starting materials for the preparation of polycyclic ketones such as the abovementioned ones; containing beside a keto-group a double bond, substances were used in the already known processes which substances, leaving out of consideration possible side-chains, have a hydroxyl group inthe position C3 and a double bond between C5 and Co. These substances have conseuently to undergo during one stage or the other of the synthesis the same chemical changes taking place in the preparation of cholestenon fromthat Schiinheimer (J. Biol. Chem. 110, 461, 1935) has described a modification of the last mentioned process in which he obtainscholestenon in a good yield starting from the cholesterol dibromide, (the intermediate product of bromination). In this way, however, the losses during 518, 1906) added to the double bond of the cholesterol the calculated quantity of bromine, this way e. g. the compounds or the cholesterolthe whole reaction are only partly avoided and, moreover, this method is notapplicable with the same successful result to substances which may be prepared by my process.

The object of my invention is/to efiect' this oxidation in a completely new and extraordinarily simple way whereby a substantially quantitative yield is obtained. I have round that unsaturated polycyclic alcohols are capable of being oxidized to the corresponding ketones by yielding 2 atoms of hydrogen per molecule and per hydroxyl group to other substances involved in this reaction and containing keto or aldehyde groups in the presence of certain 'alcoholates. At least one hydroxyl group of the unsaturated alcohol is converted into a carbonyl group. In

type are oxidized to thos'e'oi the cholestenon type and as a matter of fact in such'a delicate way that the yield is practically theoretical. My method is particularly adapted to the production of the corresponding ketones from unsaturated polycyclic alcohols containina a cyclopentanopolyhydrophe'nanthrene nucleus.

My new process is in every respect superior to the methods known till now. My process consists herein that the sterol alcohol to be oxidized is treated in the presence or tertiary metal alcoholates, preferably tertiary alcoholates or aluminium or oi magnesium chloride with an excess of hydrogen acceptor. Preferably the reaction is carried out at an increased temperature (50-140' 0.) in order to increase the reaction speed, and, moreover, in order to increase. the solubility of the intermediary reaction products in .an inert solvent, such as benzene, which may be added.

Ashydrosen acceptors I may use ketones and aldehydeso! the aliphatlc,-alicyclic and aromatic series; I

Withou such a way that, i'romthe polycyclic alcohol (I) e. g. with acetonerunder the action or the aluminium or alcoholate, an addition compound-(II) is termed whichsplits into the ya-unsaturated ketoneim) andprbpyl alcohol.

. l C-CK:

my method may, be applied to unsaturated polycyclic .hydroxy ketones in which it is theoretically possible for at least one of the hydroxyl groups contained therein to be oxidisedto a-carb'dpyl aroup (e. s. dehydroandrosteron. prestlimfitingmyproces'stoaspeciiictheory I have-assumed thatv the reaction takes place in neholon, etc. which can be 021M in flifl m.

to diketoues), as well as to unsaturated polym icihydroxy-esters (e. a. the acetate-(17) or the androstendiollfas well as to sterol alcohols (e. cholesterol); It is particularlyfsllrprising that the ester aroup or the hydroxy-esters is not aaponiiied during'this operation it is known I. yield of -8695'01' the theory.

that esters as a rule react with alcoholates under cation (vide Wihdaus and cooperators Ann. 520, 100, 1925). Also the presence oi a tertiary OH-group in the molecule is not objectionable in my process-so that it is possible to prepare by my. method e. a. methyl testosteron irom l'l-methyl andrcstendiol-(3,1'l) in a substantially theoretic yield (compare Ruzicka Heiv. Chim'. Acta 18, 1487, 1935). By means oi my new method specialsubstances can be prepared by synthesis .which could not be 'made up till now, due to the fact that durina the drastic oxidation of substances havingseveral double bonds, secondary reactions take place in the known methods. E. a. the ersostatrienon could not yet be prepared till now and its synthesis with a larae yield according to my new process is described in Example 5. For carrying the aluminium or magnesium chloride to the hydroxyl groups to be oxidized, tertiary alcohols come mainly into consideration, such as-e. g. trimethyl carbinol,

, amylene hydrate, triphenyl carbinol.

The advantages or my new process are that:

1. The yields are approximately twice-as high as in the knownprocesses. i

'2. The reaction can be eiiected very simply and requires only a very short reaction time in comparison to the known methods. 3. The method can be applied to crude concentrates with the same success. E. z. a pros'estercu concentrate can be prepared irom the mother liquors of the ketones obtained during the manufacture of the dehvdro androsteron from choles: terol or sitosterol and this was technically ab- 5 solutely impossible till now.

The unsaturated polycyclic ketones p epared in this way may be applied in-therapeutics. I

My invention is elucidated by but not at all restricted to the following examples:

1. Preparation of cholestenon from cholesterol 10 grams or cholesterol are dissolved in -150 cm. of acetone under heating and a solution of 20 grams of tertiary aluminium butylate in 300 cm. of anhydrous benzene is added hereto.

mixture is heated under reflux coolinz during 7 hours; the aluminium is removed by shakin: out with diluted sulphuric acid, the benzene layer is washed with water, dried with sodium sulphate and then evaporated to dryness. Bubstantially pure cholestenon remains behind which is obtained in crystallized form by recrystallization, e. g. from methanol in a yield 0! 90-95% of the theory.

2. Preparation of androstendion from dehvdroandrosteron 2 grams or dehydroandrosteron' are heated under reflux cooling with 2 grams'oi' aluminate oi amylene hydrate and 80 grams oi acetophenone in cm. of benzene during 14 hours. The reaction products are then hydrolized with diluted sulphuric acid and the washed and dried benzene solution isevaporated to dryness. The residue is iractionally distilled in high vacuum (cathodevacuum) and the fraction distilling over at'120- 140 C. is recrystallized from ether. Androstendion (melting point -17250.) is obtained in 3. Preparation of methyl from y! m drostendiol as gram or vl'lniethyl s-ss androete'ndiol I (a, 17) isneated under reflux coolin: during 20 Illv hours in so me s: ben'sene and 12 cm. or act'- tone with 3 grams of tertiary chloro magnesium butylate, which may be prepared by conversion of acetone with methyl magnesium chloride. The further treatment takes place as in Example 1 and methyl testosteron (melting point 160- 162 C.) is obtained in a yield of more than 75% of the theory.

4. Preparation of testosteron acetate from androstendiol acetate the theory.

5. Preparation of eraostatrienon from ergosterol 1.5 grams of ergosterol are dissolved under heating in 120 cm? of gasoline (boiling point 1oo-125 C.) and heated under reflux cooling after addition of 20 grams of acetone and 1 gram of tertiary aluminium butylate during 8 hours. The further treatment is effected as in Example 1, and 1.12 grams of crystallized ergostatrienon (M. P. l3l-132.5 C.) are obtained as needles.

What I claim is:

1. Process for the manufacture of unsaturated ketones 01 the cyclopentano polyhydrophenanthrene series from the corresponding unsaturated secondary alcohols, which comprises subjecting such alcohol to the action of an excess of a compound from the group consisting of aldehydes and ketones in the presence of tertiary aluminum butylate.

2. The process of manufacturing polycyclic ketones which comprises subjecting an unsaturated alcohol of the cyclopentano-polyhydrophenanthrene series in-which it is theoretically possible for at least one hydroxyl group to be replaced by a keto group to the action of an excess of an organic compound selected from the group consisting of aldehydes and ketones in the presence of an alcoholate selected from a class consisting of the tertiary aluminum and chloromagnesium alcoholates.

3. The process of manufacturing polycyclic ketones which comprises subjecting an unsatuated polycyclic alcohol selected from a class consisting o! the sterols, the hydroxy-ketones and hydroxy-esters of the cyclopentano-polyhydrophenanthrene series in which it is theoretically possible for at least one hydroxyl group to be replaced by a keto group to the action of an excess of an organic compound selected from the group consisting of aldehydes and ketones in the presence of an alcoholate selected from a class consisting of the tertiary aluminum and chloromagnesium alcoholates.

4. The process or manufacturing polycyclic ketones which comprises subjecting an unsaturrated organic compound selected from a class consisting of dehydroandrosteron. pregnenolon, the l'I-acetate of androstendioland cholesterol to the action of an excess of an organic compound selected from the group consisting of aldehydes and ketones in the presence 01 an alcoholate selected irom a class consisting q! the tertiary aluminum and chloro-magnesium alcoholates.

5. The process 0! manufacturing p ycyclic ketones which comprises subjecting an unsaturated secondary alcohol of the cyclopentano polyhydrophenanthrene series to the action of an excess of an organic compound selected from the group consisting of aldehydes and ketones in the presence of tertiary aluminum lautylate. V

6. The process of manufacturing polycyclic ketones which comprises subjecting an unsaturated secondary alcohol 01 the cyclopentano-polylnrdrophenanthrene series to the action 01' an excess of an organic compound selected from the group consisting of aldehydes and ketones in the presence of an alcoholate selected from a class consisting of the teritary aluminum and chloromagnesium alcoholates.

7. The process of manufacturing polycyclic ketones which comprises subjecting an unsaturated secondary polycyclic alcohol of the cyclopentanopolyhydrophenanthrene series to the action of an organic compound selected from a class consisting of aldehydes and ketones in the presence of a tertiary alcoholate selected from a class consist ing of the aluminum and chloro-magnesium alcoholates, the reaction taking place in an inert solvent and at a temperature ranging from 

